Phase IIa cross-over study of propylene glycol-free melphalan (LGD-353) and alkeran in multiple myeloma autologous transplantation

Abstract

Propylene Glycol-Free melphalan HCL for Injection (PGF-Mel) is a new formulation that incorporates Captisol, a specially modified cyclodextrin, to improve melphalan stability. In this phase IIa, open-label, randomized, cross-over design bioequivalence study, the pharmacokinetics of PGF-Mel were compared with the marketed formulation of melphalan, or Alkeran. Patients received half of the total dose of melphalan in the form of Alkeran and the other half in the form of PGF-Mel in an alternating manner. The pharmacokinetic measures were determined using WinNonlin 6.2 and bioequivalence was assessed using log-transformed systemic exposure parameters. Twenty-four patients, 11 females and 13 males, were enrolled between 4 February 2010 and 16 May 2011 at The University of Kansas Medical Center and The University of Kansas Cancer Center. The median age of enrolled subjects was 58 years (range: 48-65). All patients achieved myeloablation 3 days post autologous graft followed by successful neutrophil engraftment with a median of 11 days after transplant. Pharmacokinetic analysis showed that PGF-Mel was bioequivalent with Alkeran and also revealed that maximum plasma concentration (C max ) and area under the plasma concentration − time curve (AUC) were higher (~10%) after PGF-Mel administration. In conclusion, PGF-Mel is considered bioequivalent to Alkeran while also demonstrating a marginally higher systemic drug exposure.

High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation

“…Melphalan for injection contains propylene glycol solubilizer that has the potential to cause to renal and cardiac side effects that limit the ability to deliver higher doses. There is now a new formulation of melphalan, propylene glycol‐free, Capitsol‐enabled melphalan, which has been shown to be bioequivalent to melphalan for injection in myeloma patients undergoing ASCT, but it does produce 10% higher AUC values . It is likely that our results showing an association between high AUC and improved survival are also applicable to Capitsol‐enabled melphalan.…”

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation

“…melphalan as 2 doses of EVOMELA (100 mg/m 2 each, infusion time of approximately 30 minutes) on days À3 and À2 followed by a day of rest before ASCT was performed on day 0 ( Figure 1). The decision to dose melphalan over 2 days was based on the regimen used in the previously conducted phase IIa study in which propylene glycol-free melphalan HCl was shown to be bioequivalent to Alkeran; prior prospective studies have used the 2-day dosing regimen and authorities in the field consider both dosing regimens to be equivalent [14,21,22].…”

“…Propylene glycol-free melphalan hydrochloride (EVOMELA; Spectrum Pharmaceuticals, Inc., Irvine, CA, USA) is a new formulation of melphalan that incorporates Captisol (Ligand Pharmaceuticals, Inc., La Jolla, CA, USA), a specially modified cyclodextrin that improves the solubility and stability of melphalan [13,14]. This new formulation eliminates the risk of propylene glycol toxicities by using the Captisol technology used in the formulation of 6 other US Food and Drug Administrationeapproved human parenteral drugs (Vfend, Nexterone, Geodon, Abilify, Kyprolis, and Noxafil) [15][16][17][18][19][20].…”

“…The objective of this study was to confirm the safety and efficacy of high-dose EVOMELA as a myeloablative conditioning regimen in patients with MM undergoing ASCT. Propylene glycol-free melphalan HCl has been previously shown to be bioequivalent to Alkeran in a phase IIa study [14].…”

Comparison of Generic and Original Melphalan for Engraftment and Toxicity in Autologous Stem Cell Transplantation

“…Aljitawi ve arkadaşları tarafından yapılan 24 hastalık faz II çalışmada, miyeloablasyon otolog naklin üçüncü gü-nünde, nötrofil engraftmanı ortanca 11. günde olmuştur. Farmakokinetik olarak propilen glikol içermeyen melfalan alkeran ile biyoeşdeğer olarak bulunmuştur (8).…”